Abstract
Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset of cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A key issue in the field is the need to understand why these cytokines are transcriptionally activated in the patients. Here, we have examined several transcription units subject to pathological reactivation in MS, including the TNFα and IL8 cytokine genes and also several Human Endogenous RetroViruses (HERVs). We find that both the immune genes and the HERVs require the heterochromatin protein HP1α for their transcriptional repression. We further show that the Peptidylarginine Deiminase 4 (PADI4), an enzyme with a suspected role in MS, weakens the binding of HP1α to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. The resulting de-repression of both cytokines and HERVs can be reversed with the PADI-inhibitor Cl-amidine. Finally, we show that in peripheral blood mononuclear cells (PBMCs) from MS patients, the promoters of TNFα, and several HERVs share a deficit in HP1α recruitment and an augmented accumulation of histone H3 with a double citrulline 8 tri-methyl lysine 9 modifications. Thus, our study provides compelling evidence that HP1α and PADI4 are regulators of both immune genes and HERVs, and that multiple events of transcriptional reactivation in MS patients can be explained by the deficiency of a single mechanism of gene silencing.
Highlights
Multiple Sclerosis (MS) is a progressive inflammatory disease of the central nervous system in which leukocytes and antibodies attack myelin sheaths, resulting in demyelination and destruction of the axons [1]
We find that the repressor protein HP1a is present on the promoter of both types of transcription units in normal cells and that the recruitment of this protein to these promoters is decreased in MS patients
We show that the delocalization of HP1a from these promoters can be caused by citrullination of histone H3, and we provide evidence indicating that levels of this histone modification is augmented in MS patients
Summary
Multiple Sclerosis (MS) is a progressive inflammatory disease of the central nervous system in which leukocytes and antibodies attack myelin sheaths, resulting in demyelination and destruction of the axons [1]. In MS patients, activation of the T cell population is associated with increased expression of a series of cytokines [3,4]. In MS and other autoimmune diseases including Rheumatoid Arthritis and Systemic Lupus Erythematosus, transcription of Human Endogenous RetroViruses (HERVs) is increased in T cells [5,6,7]. HERVs are abundant vestigial retroviral sequences that in healthy cells are largely silenced by the epigenetic mechanisms repressing most repeated DNA sequences. These mechanisms include DNA methylation and histone H3 lysine 9 (H3K9) methylation. DNA methylation at ERV promoters is high in differentiated mouse cells [10], while it may be partially dispensable in mouse embryonic stem (ES) cells [11]
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